The delivery of interfering RNAs to lung tissue provides an opportunity to develop novel anti-viral and anti-inflammatory therapies for a variety of lung disorders. Intratracheal delivery of constructs for RNA interference (RNAi), as has been used to block influenza and parainfluenza lung infections, is a particularly exciting approach to treating lung disease because it offers potentially tissue-specific delivery of these molecules to a target organ. However, the cell types transduced with these methods are not yet known, and some investigators have found concerning non-specific effects in non-pulmonary tissues of mice exposed to this route of delivery. In addition, the potential for adverse effects in the lung, such as activation of inflammation are concerns that limit application of RNAi technology. Cell-specific, tissue-specific delivery of RNAi to immune cells within the lung would be a significant advance enabling potential treatment of many diseases characterized by inflammation, including asthma and emphysema. This grant application presents preliminary data demonstrating a novel lentiviral-based system that allows the cell-specific, tissue-specific in vivo delivery of RNAi to resident alveolar macrophages. The specific aims of this proposal are designed to test the efficacy of this targeted in vivo delivery method and to understand the biology of this system, including screening for specificity and potential off-target effects. Finally, the system is applied for in vivo knockdown of NF-kB signaling in mouse alveolar macrophages and the treatment of tobacco smoke- induced lung inflammation. [unreadable] [unreadable] [unreadable]